新型组织蛋白酶L抑制剂偶联物的设计、合成及生物活性研究

The delivery of a small-molecule anticancer agent into malignant tumors in a highly effective and highly selective way is a major challenge in successful chemotherapeutic intervention in cancer. This project advanced three new inhibitors (those are extremely cytotoxic against Cathepsin L) by imparting selectivity through two targeting strategies. For the first strategy, these highly potent thiosemicarbazone-based inhibitors (named as Cat-1,Cat-2,Cat-3) will be conjugated to short amino acid sequences, which are designed for selective cleavage by specific protease enzymes that are more abundant in the tumor microenvironment. As inhibitor-conjugate, it is anticipated that these analogues will be inert in terms of biological activity, however selective cleavage in the tumor microenvironment will release the potent cytotoxic agent (Cat-1,Cat-2 or Cat-3) resulting in selective delivery. For the second strategy, these three inhibitors will be conjugated through appropriated linkers to a proprietary antibody that selectively targets phosphatidylserine exposed on tumor cells themselves. It is anticipated that the combination of targeted tumor damage by the antibody itself and the extreme cytotoxicity imparted by the selective delivery of Cat-1,Cat-2 and Cat-3 will result in highly potent therapeutic efficacy. Collectively, this project will investigate some pratical strategies in improving the stability of inhibitors in blood circulation and allowing efficient cytotoxic inhibitors release within tumor cells.

高效高选择性的释放小分子抗肿瘤试剂到恶性肿瘤部位是成功化学治疗癌症面临的一个主要挑战。本项目通过两个靶向策略提高了三个抑制剂的选择性释放（三个抑制剂对组织蛋白酶L均显示很强的毒性）。第一个策略，氨基硫脲的抑制剂（被命名为Cat-1，Cat-2，Cat-3）被偶联到短的氨基酸序列上，这些序列可被肿瘤微环境中大量存在的特定的蛋白水解酶选择性裂解。作为抑制剂偶联物，这些化合物是没有生物活性的，然而在肿瘤微环境中将释放毒性小分子（Cat-1，Cat-2，Cat-3）实现选择性给药。第二个策略，这三个抑制剂通过适当的接头被偶联到抗体上，该抗体选择性靶向裸露在癌细胞外膜的磷脂酰丝氨酸。抗体本身对靶向肿瘤的损害和选择性释放Cat-1，Cat-2，Cat-3带来的毒性结合在一起将会产生良好治疗效果。总之，本项目将探讨提高抑制剂在血液循环中的稳定性和允许毒性抑制剂在肿瘤细胞中高效释放的一些实际策略。

缩胺基硫脲类化合物是一个拥有多种结构的大家族并且展示多种优良的生物活性，尤其是抗肿瘤活性。本项目首先研究了6-氟-8-氯硫代色满-4-酮缩胺基硫脲化合物对乳腺癌MCF-7细胞的抑制作用并探讨其潜在的引发乳腺癌细胞MCF-7凋亡的机理；其次合成了硫代色满-4-酮缩氨基硫脲, 1,1-二氧硫代色满-4-酮缩氨基硫脲和苯并噻氮卓缩氨基硫脲三个系列的化合物并对其抑制细胞增殖的活性进行评价， 构效关系显示，含有8-位取代基的硫代色满-4-酮框架有利于增强缩氨基硫脲化合物的抗肿瘤活性。此外通过用N原子替代硫代色满-4-酮缩氨基硫脲的1-位的硫原子，筛选出8-溴-2,3-二氢-喹啉-4-酮缩氨基硫脲， 该化合物对乳腺癌细胞MCF-7、黑色素瘤细胞SK-mel-2和前列腺细胞DU145的抑制作用均优于顺铂。总之，本项目围绕硫代色满-4-酮缩胺基硫脲类化合物和与其相关的化合物的抗肿瘤活性及诱发细胞凋亡的机理进行研究，旨在为开发新的潜在抗癌药物提供有益的信息。

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